Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2002 — 1/7
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2002 - 1/7
`
`

`

`-
`
`Agenda
`
`Volume 10 Number 11
`November 1998
`
`4
`
`8
`
`12
`
`18
`
`27
`
`32
`
`43
`
`70
`
`74
`
`76
`
`Photography: Phototechnics, Chester, UK.
`Art direction: Pet er Fielder·Shaw
`
`Publisher
`Clair S. Whilecross
`(cwhilecross@advanslar.com)
`Editor
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`(krobinson@advanstar.com)
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`Julian Upton
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`Brussels Report - Guidelines for Christmas Shopping
`Albedo
`The new EMEA notes for guidance on product development dictate
`more guidelines to pharmaceutical technologists, with considerable
`application to anticancer drugs
`
`Washington Report - Costs, Coverage and Commercials
`Jill Wechsler
`As spending on prescription drugs increases and health plan coverage
`changes, FDA looks to find ways to monitor marketing without
`interfering with the flow of information concerning new products
`
`3
`
`Mercury-Free Determination of Apparent Density and Porosity
`of Pellets by Powder Pycnometry
`Firas El Saleh and Peter Kleinebudde
`Powder pycnometry is evaluated as an alternative, mercury-free
`method for the determination of apparent density and porosity,
`important parameters in the development and production of pellets
`
`Wet Granulation - Fluidized Bed and High Shear Techniques
`Compared
`Ole W0rts
`Two types of wet granulators are discussed, with particular
`attention given to granule growth mechanisms, the characteristics
`of the final product and the number of unit operations in each
`process
`
`HPMC Capsules - An Alternative to Gelatin
`Toshihiro Ogura, Yoshihiro Furuya and Seinosuke Matsuura
`The benefits of HPMC compared with gelatin capsules are suggested,
`which include an absence of chemically reactive groups, low
`moisture content and the ability to maintain mechanical integrity
`under low-moisture conditions
`
`BioPharm Europe
`The Technology & Business of Biopharmaceuticals
`
`lnterphex Showcase
`A look at some of the products and setvices available at Interphex
`Europe
`
`Product Showcase
`
`Literature Review
`
`78
`
`68
`
`Classified & Recruitment
`
`Advertisers Index
`
`Next Issue
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`Manuscripts
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`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2002 - 2/7
`
`

`

`HPMC CAPSULES
`
`HPMC Capsules - An Alternative
`to Gelatin
`
`32
`
`Hydroxypropyl methy/cellu/ose (HPMC) capsules are made of plant-derived
`materials and do not contain components of animal origin, eliminating
`problems with religious or vegetarian dietary restrictions. Unlike gelatin,
`HPMC does not have chemically reactive groups, dramatically decreasing
`the potential tor reactions between the drug and the capsule shell. HPMC
`capsules have a naturally low moisture content, maintain mechanical
`integrity under extremely low-moisture conditions and are, therefore, ideally
`suited tor use with formulations containing water-unstable drugs.
`
`Toshihiro Ogura, *
`Yoshihiro Furuya
`and Seinosuke
`Matsuura
`
`Toshihiro Ogura is the general
`manager and Yoshihiro Furuya is a
`researcher at the Formulation R&D
`Laboratories, Shionogi & Co. Ltd,
`2-1-3, Kuise Terajima, Amagasaki,
`Hyougo 660-0813, Japan.
`Tel. +81 6 401 8331
`Fax +81 6 401 4593
`Seinosuke Matsuura is a researcher
`with Shionogi Oualicaps, 321-5
`lkezawacho, Yamatokoriyama, Nara
`639-1032, Japan.
`
`*To whom all correspondence should
`be addressed.
`
`H ard capsules were developed as
`
`an edible container to mask the
`taste and odour of medicines. As
`a result of the introduction of mass(cid:173)
`production techniques and high-speed
`capsule filling machines, capsules have
`become one of the most popular
`dosage forms for pharmaceuticals. Cap(cid:173)
`sules have traditionally been used for
`powder or granule formulations, but in
`recent years have been adapted to
`contain oily liquids, tablets and even
`powders for inhalation. Capsules enjoy wide(cid:173)
`spread popularity because of their relative ease of
`manufacture (compared with other dosage forms
`such as tablets) and flexibility of size to accom(cid:173)
`modate a range of fill weights. They are readily
`able to achieve bioequivalence between different
`strengths of the same formulation.
`Capsules do have some drawbacks. Capsule
`shells made from gelatin, the main material used
`for this purpose, generally contain 13-15% water
`and therefore may not be suitable for use with
`readily hydrolysable drugs. Some drugs may react
`with the amino groups of gelatin, causing dis(cid:173)
`colouration or formation of crosslinks between
`gelatin molecules, which retard capsule dissolu(cid:173)
`tion. Gelatin products are sometimes shunned as a
`result of religious or vegetarian dietary restrictions.
`For these reasons, work is under way to develop
`capsules made of starch, cellulose or polyvinyl
`alcohol/vinyl acetate mixtures. Yamamoto et al.
`recently succeeded
`in making capsules from
`hydroxypropyl methylcellulose 2910 (HPMC), 1 a
`material also used as a water-soluble film coating.
`We have confirmed the applicability of the H PMC
`capsule to products. 2 As USP, EP and JP (the
`United States, European and Japanese pharma(cid:173)
`copoeia) monographs all describe capsules made of
`cellulose or methylcellulose, in addition to gelatin,
`the H PMC capsule conforms to pharmacopoeial
`standards.
`
`Artwork by Peter Fielder-Shaw.
`
`Manufacturing HPMC capsules
`HPMC capsules can be manufactured by the
`dipping and forming method, employed for the
`manufacture of hard gelatin capsules. Shaped pins
`are dipped into a solution of HPMC, after which
`the HPMC film is gelled, dried, trimmed and
`removed from the pins. The body and cap pieces
`are then joined. As HPMC alone does not gel at low
`temperatures greater than 60 oc
`temperatures -
`are required -
`small amounts of carrageenan, a
`natural gelling agent widely used in the food
`industry, and potassium chloride, a gelling
`promoter, are added.
`
`Physical characteristics of HPMC capsules
`The HPMC capsule is odourless and flexible, and
`exhibits similar dis solution behaviour to the
`gelatin capsule. Its appearance is the same, except
`that it lacks the lustre of gelatin . The physical
`properties of both HPMC and gelatin capsule shells
`that may affect stability and dissolution, and
`therefore their suitability for use with various
`formulations and intended use, are listed in Table I.
`Capsule hardness. There are two components of
`capsule shell hardness - brittleness and tolerance
`to deformation - which determine suitability for
`use with automated encapsulating machines, as
`well as end use. When the moisture content of the
`capsule shell is decreased, as may occur when a
`desiccant is added to a package of capsules
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2002 - 3/7
`
`

`

`34
`
`HPMC CAPSULES
`
`containing moisture-labile drugs, gelatin
`capsules tend to become brittle and are
`subject to breakage during transport and
`storage. The relationship between brittleness
`and moisture content can be determined
`using a hardness tester (Figure 1). The results
`of our testing show that the percentage of
`broken gelatin capsules sharply increases as
`the moisture content of the hard gelatin shell
`drops below 10%, although the degree of
`brittleness can be modified somewhat by
`addition of polyethylene glycol (PEG) during
`manufacture. In contrast, no brittleness was
`observed in HPMC capsule shells even at
`moisture levels of only 2% (Figure 2a).
`Tolerance of the capsule shell to denting
`or deformation was estimated, using the
`same testing device, by determining the
`falling distance necessary for a 7 g weight to
`cause deformation in 50% of the capsules
`tested. As can be seen in Figure 2b, toler(cid:173)
`ance (resistance) of both types of capsules
`to deformation increased with decreasing
`moisture content. The two types of capsules
`show equivalent tolerance to deformation at
`their average moisture content levels
`2-5% for HPMC capsules and 13-15% for
`gelatin capsules.
`Performance during test runs on a capsule
`filling machine. Results of the hardness test(cid:173)
`ing suggested that HPMC capsules would be
`acceptable for use with automated capsule
`filling machines. Capsule filling tests were
`conducted with encapsulators, the results of
`which are summarized in Table II. Filling
`defects, such as deformation, splits, dents or
`cracking, occurred at frequencies of less than
`0.03%, a rate similar to that observed when
`filling hard gelatin capsules.
`
`Biopharmaceutical characteristics
`Cephalexin, which is mainly absorbed from
`the duodenum, was used as the model
`
`formulation to compare capsule dissolution
`and drug absorption from gelatin and HPMC
`capsules.
`Dissolution from capsules. Dissolution testing
`(Figure 3) was performed with solutions of
`various pHs using
`the paddle method
`described in the JP. Results of testing in the
`JP 'first test fluid' (pH 1.2) and a solution of
`pH 4 (Figures 3a and b) showed no signifi(cid:173)
`cant differences in the dissolution behaviour
`of either type of capsule. When using the JP
`'second test fluid' (pH 6.8; Figure 3c), both
`types of capsules achieved approximately
`100% dissolution. Dissolution times for the
`H PMC capsule, however, were approximately
`5 min longer than those for the gelatin
`capsule, because of the formation and
`persistence of a very friable gel membrane
`surrounding the drug fill. The presence of
`potassium, a known promoter of carrageenan
`gelation, in the JP second test fluid was
`suggested to be the cause of this membrane
`formation.
`Subsequent testing of the two capsule
`types in various buffer solutions (pH 6.8) that
`did not contain potassium or in plain disti lled
`water showed no difference in dissolution
`times,
`thus supporting our hypothesis
`(Figure 3d). As the cation concentration in
`the gut is low, test solutions that do not
`contain potassium, such as Mcilvaine buffer
`(pH adjusted over a range of 3.0-7.5 by
`addition of up to 0.05 M disodium hydrogen
`phosphate and 0.025 M citric acid), or one of
`the pH 6.8 test solutions listed in the USP for
`enteric formulations, might be considered
`acceptable alternatives for determining rates
`of dissolution.
`Human studies of cephalexin rates of
`absorption from HPMC and gelatin capsules.
`HPMC and gelatin capsules containing
`250 mg of cephalexin, together with 100 ml
`of water, were administered to six healthy
`
`Table 1: Physical properties of capsule shells made of HPMC and gelatin.
`
`Moisture content
`
`Water vapour permeability
`
`Substrate for protease
`
`Maillard reaction with drug fill
`
`Deformation by heat
`
`2-5%
`
`Low
`
`No
`
`No
`Above - 80 ·c
`
`Water dissolution at room temperature
`
`Soluble
`
`Static
`
`Light degradation
`
`Low
`
`No
`
`13-15%
`
`Low
`
`Yes
`
`Yes
`Above - 60 ·c
`(degradation)
`
`Insoluble
`
`High
`
`Possible
`
`I
`
`Weight
`
`· ·- ---- ---------t
`!
`
`~
`cc::D- ------------
`
`Capsule
`
`Figure 1: Hardness tester for capsules.
`
`(a)
`
`c:
`Q)
`-""
`e
`..0 e:,
`
`Vl
`Vl
`
`Q)
`
`Q) c:
`E
`·c
`c:c
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`15
`10
`5
`0
`Moisture content of capsule (%)
`
`HPMC
`-o- Gelatin
`-fi- Gelatin with PEG
`
`(b)
`
`~ 40
`E
`.:::..
`Q)
`u
`c:
`
`30
`
`20
`
`10
`
`0
`
`0
`20
`5
`15
`10
`Moisture content of capsule (%)
`-o- Gelatin
`- ~ HPMC
`
`"' ...,
`:.0
`t:n c:
`
`Vl
`
`:.s "' w...
`
`Figure 2: Test results of mechanical integrity of
`HPMC and gelatin capsules at various levels of mois(cid:173)
`ture content. (a) Brittleness; falling distance of a 50 g
`weight is 10 em {b) Tolerance to deformation; falling
`distance of a 7 g weight, deforming 50% of capsules.
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2002 - 4/7
`
`

`

`HPMC CAPSULES
`
`Table II: Performance of encapsulators with HPMC capsules.
`
`J
`
`Hofliger and Karg
`Hofliger and Karg
`Harro Hofliger
`Shionogi Qualicaps
`
`36
`
`GKF1000
`GKF1000
`KFM1
`LIQFIL super80
`
`36000
`60000
`3600
`80000
`
`• I
`
`120000
`500000
`3000
`40000
`
`< 0.001
`0.001
`< 0.03
`< 0.003
`
`Pellicle formation, however, still represents
`the potential for dissolution problems, and
`investigations are under way
`to
`find
`stabilizers that would prevent formation of
`crosslinks between gelatin molecules. A
`practical alternative is to employ H PMC
`capsules as a means to completely avoid the
`formation of insoluble membranes. Matsuura
`and his team have demonstrated the value of
`this approach by filling both hard gelatin and
`HPMC capsules with spiramycin, a macrolide
`antibiotic known to cause insolubilization of
`gelatin capsules. 6 After storage for 10 days
`under conditions of 60 °C and 75% relative
`humidity, the gelatin capsules did not disin(cid:173)
`tegrate, whereas the H PMC capsules were
`unaffected (Table III).
`
`Addressing potential discolouration problems.
`Capsules filled with substances containing
`aldehyde groups, such as ascorbic acid, will
`become brown by discolouration under high
`temperature/humidity conditions. This
`is
`thought to be the result of a reaction
`between ascorbic acid and the a-amino
`group on the gelatin protein, as depicted in
`Figure 5. To minimize discolouration reac(cid:173)
`tions with these types of substances, either
`the moisture content of the gelatin capsule
`shell must be lowered andjor the capsules
`must be stored in moisture-proof containers.
`H PMC does not contain reactive groups,
`thereby minimizing discolouration problems
`that occur as a result of interactions between
`the drug and capsule shell. To confirm this,
`
`volunteers under fasting conditions, and
`drug plasma concentrations were deter(cid:173)
`mined. As
`illustrated
`in Figure 4, drug
`concentration profiles were similar, and no
`significant differences were observed in total
`drug absorbed (AUC, area under the plasma
`level curve), peak plasma concentrations
`(Cmax) or time to reach peak plasma
`concentrations (tmax).
`
`Application to formulations
`Some drugs react with gelatin, which may
`prolong dissolution or result in discoloura(cid:173)
`tion of the capsule shell during storage.
`Other drugs become hydrolysed by the mois(cid:173)
`ture contained in the gelatin capsule shell.
`H PMC is not only chemically inert, but has a
`lower moisture content (2-5%), permitting
`maintenance of a low humidity environment
`within the HPMC capsule shell.
`Addressing potential prolonged dissolution
`problems. Drugs containing aldehyde groups,
`or produdng aldehydes on decomposition,
`promote crosslinking between gelatin pro(cid:173)
`teins, 3 forming a thin insoluble membrane
`called a pellicle4 that may delay dissolution. If
`the membrane is disrupted by the mechanical
`forces of gastric emptying or is broken down
`by digestive enzymes, its formation would
`not affect absorption and bioavailability of
`the drug. The US Food and Drug Administra(cid:173)
`tion (FDA)/Industry Gelatin Capsule Working
`Group, in fact, concluded that formation of
`an insoluble membrane could be considered
`to have a negligible impact on drug bioavail(cid:173)
`ability if the capsules dissolved during the
`'two-tiered dissolution test; which employs a
`medium containing digestive enzymes. 5
`
`Table Ill: Disintegration test results of HPMC and
`gelatin capsules filled with a macrolide antibiotic
`and stored at 60 ·c. 75% RH for 10 days.
`
`HPMC capsule
`Gelatin capsule
`
`4.6
`3.3
`
`4.5
`>30
`
`Figure 3: Comparison of dissolution of cephalexin in various media from HPMC and gelatin capsules
`{JP paddle method, 100 rpm).
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2002 - 5/7
`
`

`

`HPMC CAPSUlES
`
`------ J
`
`15
`
`10
`
`40
`
`~ 5
`E
`'-Cl
`::i.
`
`t:
`0
`·.p
`~ ...,
`t:
`QJ
`u
`t:
`0
`u
`
`"' E
`V1
`.!9
`a..
`
`0
`
`15
`
`10
`
`5
`
`0
`
`0 1 2 3 4 5 6 7 8
`
`0 1 2 3 4 5 6 7 8
`
`15
`
`10
`
`5
`
`0
`
`15
`
`10
`
`5
`
`0 1 2 3 4 5 6 7 8
`
`H PMC capsule
`Gelatin capsule
`
`0 1 2 3 4 5 6 7 8
`
`15
`
`10
`
`5
`
`0
`
`15
`
`10
`
`5
`
`0 ~ 0
`
`0 1 2 3 4 5 6 7 8
`
`0 1 2 3 4 5 6 7 8
`
`Figure 4: Comparison of plasma profiles of cephalexin, administered in HPMC and gelatin capsules to healthy volunteers under fasting conditions {dose 250 g, n = 6).
`
`Time (hr)
`
`HPMC and gelatin capsules were filled with
`ascorbic acid, packed in polyethylene bottles
`without a desiccant, and stored at 40 °(/75%
`relative humidity for two months. The gelatin
`capsules took on a brown discolouration,
`whereas the colour of the H PMC capsules did
`not change (Figure 6). In both cases, the
`colour of the ascorbic acid in the capsules did
`not change, indicating that the discolouration
`was the result of a reaction between the
`ascorbic acid and the gelatin shell.
`Addressing potential problems with readily
`hydrolysable drugs. When aspirin alone
`was filled into gelatin capsules and stored
`under extreme
`temperature conditions
`
`(60 °C) for 2 weeks, the aspirin content of
`the drug fill decreased to 85% of its initial
`concentration, apparently as a result of
`hydrolysis. In contrast, when aspirin was
`filled into HPMC capsules, the aspirin con(cid:173)
`centration in the drug fill did not decrease
`to less than 95% of its initial concentra(cid:173)
`indicating greater stability when
`tion,
`stored in H PMC capsules.
`When the two capsule types were filled
`with aspirin combined, in a ratio of 1:1,
`with partially pregelatinized starch, after
`2 weeks, the aspirin content was at 98% of
`the initial concentration and no visible
`changes appeared on the surface of the
`
`capsule. Carboxymethylcellulose calcium
`(CMC-Ca) conferred a similar stabilizing
`effect. This is believed to be the result of
`the ability of both pregelatinized starch
`and CMC-Ca to readily absorb any moisture
`released by the capsule shell. Conversely,
`additives with a high moisture content,
`such as corn starch or microcrystalline
`cellulose (MCC), enhance aspirin hydrolysis.
`capsules have
`a
`Although HPMC
`naturally low moisture content, the HPMC
`film does contain some adsorbed water that
`is readily released. For drugs
`that are
`extremely moisture sensitive, it may still be
`desirable to add water absorbent excipients
`
`,"Q'
`
`0
`0
`Dehydroascorbic acid
`
`+
`a -Ami no acid
`
`OH
`
`OH
`
`"/:),
`
`R= -CH-CH2
`I
`I
`OH OH
`
`Ascorbic acid
`
`~H
`,"(:('
`--- KQ 0
`
`0
`
`OH
`
`I
`
`l)H R
`HO
`0
`
`OH
`
`NH2
`
`~-A1H
`O
`0 OH H
`
`Scorbamine acid
`
`Radical reaction
`
`Yellow compounds
`
`Browning
`
`Figure 5: Possible mechanism of gelatin discolouration resulting from reaction between ascorbic acid and gelatin a -amino groups.
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2002 - 6/7
`
`

`

`HPMC CAPSULES
`
`I
`
`Room
`temperature
`
`40 "C. 75% RH
`
`42
`
`Gelatin
`
`HPMC
`
`Figure 6: Comparison of discolouration of HPMC and gelatin capsules filled with ascorbic acid (stored in
`polyethylene bottles for 2 months).
`
`to the formulation and desiccants to the
`container to enhance stability. Hydroxy(cid:173)
`propyl methylcellulose (HPMC) capsules, as
`described in this article, are particularly well
`suited to these situations because they resist
`becoming brittle under
`low humidity
`conditions.
`
`Other applications
`Capsules are widely used by the health food
`industry. As is seen with traditional phar(cid:173)
`maceuticals, gelatin capsules filled with
`various herbs and extracts may cause cap(cid:173)
`sule discolouration. HPMC capsules would be
`an excellent substitute in these situations.
`
`Soon at a theatre near you ...
`
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`.] r.~., \ J-r r "
`~J n c u l J P ~ o IJ rs e~
`8ernn
`
`Featuring among others: Mr John Y. Lee
`
`For profession als in the European pharmaceutical and
`biotech industry, Lunden/Ellow presents a GMP course
`program intended to give knowledge in GMP Inter(cid:173)
`pretations and Applications as well as Compliance and
`Regul atory issues.
`
`Check out th e European course calend ar at
`
`::=
`
`Helsinki
`
`Paris
`London
`
`Geneva
`
`A Key to Compliance
`
`LundeniEIIow ab, P.O. Box 1082, SE-181 22 Lidingii, Sweden
`Ph one +46-8767 4440. Fax +46-8767 4514. E-maillunden@ellow.se
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`CIRCLE 26
`
`Capsules have also been used as unit(cid:173)
`dose containers to administer finely divided
`powders with specially designed inhalation
`devices. In the past, such delivery systems
`have encountered problems, including adher(cid:173)
`ence of the powder to the gelatin capsule
`because of static electricity and capsule
`breakage because of the brittleness that
`results from storage under very low humidity.
`The H PMC capsule avoids these problems
`and would be appropriate for use in these
`situations.
`Unlike gelatin capsules, H PMC capsules
`dissolve in water at temperatures as low as
`10 oc, extending its potential to agricultural
`use, for example, for chemicals applied to
`paddy fields.
`
`Conclusion
`HPMC does not have chemically reactive
`groups such as those in gelatin, dramati(cid:173)
`cally decreasing the potential for interaction
`between filled drug and capsule shell.
`HPMC has a naturally low moisture con(cid:173)
`tent, maintains mechanical integrity under
`extremely low-moisture conditions, such as
`that created by addition of water adsorbent
`excipients, and is therefore ideally suited for
`use with formulations containing water(cid:173)
`unstable drugs.
`Dissolution profiles of H PMC and gelatin
`capsules are comparable over a wide range of
`pH values. Human studies show that oral
`bioavailability of cephalexin
`in HPMC
`capsules is identical to that delivered in
`standard gelatin capsules.
`
`References
`1. T. Yamamoto, K. Abe and S. Matsuura,
`"Hard Capsule for Pharmaceutical Drugs
`and Method for Producing the Same," US
`Patents 5,264,223 and 5,431,917.
`2. T. Ogura et al., "New Cellulose Capsules,"
`Pharm. Tech. Japan 14(3), 391-400
`(1998).
`3. G.A. Digenis, T. B. Gold and V. P. Shah,
`"Crosslinking of Gelatin Capsules and its
`Relevance to Their In Vitro-In Vivo Per(cid:173)
`formance," J. Pharm. Sci. 83(7),
`915-921 (1994).
`4. J.T. Carstensen and C.T. Rhodes, "Pellicle
`Formation
`in Gelatin Capsules," Drug
`Dev.
`Ind. Pharm. 19(20), 2709-2712
`(1993).
`Symposia
`5. AAPS Annual Meeting,
`Abstracts (2 November 1997, Boston,
`Massachusetts, USA) pp 99-103.
`6. S. Matsuura and T. Yamamoto, "New Hard
`Gelatin Capsules Prepared from Water(cid:173)
`Soluble Cellulose Derivative," Yakuzaigaku
`53(2), 135-140 (1993). ~
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2002 - 7/7
`
`